ESTROGEN DEPRIVATION CAUSES ESTRADIOL HYPERSENSITIVITY IN HUMAN BREAST-CANCER CELLS

Genetic and environmental factors can modulate the level of sensitivit y to various hormones, including estrogens. Enhanced sensitivity to es tradiol (E(2)) has been demonstrated in several biological conditions, such as in sheep during the nonbreeding season, in untreated patients with Turner's syndrome, and in the prepubertal state in normal girls. We postulated that secondary responses to hormonal therapy in patient s with breast cancer could also result from on hanced E(2) sensitivity , developing as an adaptive mechanism to E(2) deprivation. The present study used the MCF-7 human breast cancer cell line as a model system to test the concept that enhanced sensitivity to E(2) may occur as a r esult of adaptation to low E(2) levels. After depriving MCF-7 cells of estrogens in tissue culture medium for periods of 1-6 months, we esta blished conditions under which replication could be stimulated maximal ly by 10(-14)-10(-15) mol/L E(2). In contrast, wild-type cells not exp osed to estrogen deprivation required 10(-10) mol/L E, to grow at the same rate. Further, the concentration of the antiestrogen, ICI 164384, needed to inhibit growth by 50% in estrogen-deprived cells was much l ower than that required in wild-type cells (i.e. 10(-15) vs. 10(-9) mo l/L). Nude mice implanted with these estrogen-deprived cells demonstra ted an earlier appearance of palpable tumors in response to E(2) than animals bearing wild-type cells. Reexposure to 10(-10)-10(-9) mol/L E( 2), either in vivo or in vitro, returned these cells to the level of e strogen sensitivity observed in wild-type cells. Taken together, these observations suggest that breast cancer cells can adapt to low levels of estrogens by enhancing their sensitivity to E(2).